It is generally believed that controlled drug delivery is capable of improving the safety and clinical efficacy of cancer chemotherapeutic drugs, which typically produce severe side effects due to non-specific toxicity. One approach to this problem is to preferentially deliver cytotoxic drugs to the tumour. It has been established by several research groups that nanospherical particles in the 50-250 nm diameter range, possessing the appropriate physico-chemical properties, can be selectively distributed into tumour masses from the general circulation, over a period of one to two days after intravenous injection. This occurs by virtue of the aberrant structure of the micro-vasculature within many tumours. Various types of nanoparticulate delivery systems have been used experimentally but most have significant limitations that have precluded their final use for medical applications.
The major limitations are as follows:                1) Their physical stability is too poor to provide long enough blood circulation to ensure accumulation into the tumour (e.g. liposomes),        2) The rate of release from most types of nano-particles is too fast to provide a concentrated dose to the tumour,        3) The stable nano-particles developed to date have very low drug loading and slow release rate which are insufficient to deliver the appropriate therapeutic dose,        4) Many types of nanoparticulate systems are rapidly detected by the immune system (i.e. reticulo-endothelial system) and eliminated from the blood stream, resulting in a small proportion of the drug reaching the tumour.        
Most of the materials used as drug delivery vehicle are organic in nature: polymers, liposomes, dendrimers, etc. In contrast, the ceramic materials provide many advantages over the organic delivery matrices. For example silica particles are biologically inert and have hydrophilic surfaces. They are also non-toxic, highly biocompatible and can be synthesised at low temperature in order to preserve the molecular structure of the drug. Furthermore, their size and porosity remain stable within a wide range of chemical environment. Sol-gel technology, an inorganic room temperature polymerisation technique (see FIG. 1), has been used to successfully encapsulate organic molecules inside oxide matrices.
During the last several years, the present inventors have developed a technology for producing ceramic particles for controlled release applications (WO01/62332). This technology allows active molecules to be encapsulated in ceramic particles using a combination of sol-gel chemistry and water-in-oil (W/O) emulsion synthesis. The size of the particle is controlled by the size of the emulsion droplets and the release kinetics is controlled by the sol-gel chemistry. To produce monodisperse nanoparticles using this method, stable micro-emulsions are used. In such systems, the water droplet size is usually restricted to several to a few tens of nanometers limiting the final particle size to less than 100 nm even in the presence of important Ostwald ripening. Larger particle sizes can be obtained using unstable emulsion systems but the resulting particles present a broad size distribution which is undesirable in such application as for example the passive targeting of tumours where a precise control over the particle size is desirable. Although such a precise control over the size can be achieved using the Stöber process (seeded growth in diluted media), this type of process does not provide the compartmentalisation achieved in emulsions which is necessary to ensure encapsulation of the active materials during gelation. Thus the Stöber process is inadequate for the synthesis of particles for controlled release applications. Another limitation of the technology outlined in patent WO01/62332 is its inability to produce particles with delayed, sequential or pulsed release sequences. Once the ceramic particles are introduced in a liquid, they start to release immediately. This disadvantage might be overcome by producing a core-shell structure with the active molecule located in core surrounded by an empty shell which acts as a diffusion barrier and prevents the active to leach rapidly.
Substantial work has been performed during the last decade to try to achieve complex and tailored release pattern of active molecules from specific matrices. The delayed-release, timed-release, or sequential release of drug(s) from a variety of delivery vehicles have been investigated. To achieve these complex release patterns, the delivery system is either based on the modification of physico-chemical properties of the delivery materials or the modification of the morphology of the system such as using multi-layered structure. All these systems use an organic matrix in various forms: polymer gel, liposome, fibre, microcapsule, tablet etc. Particles, and more specifically nanoparticles, have not been investigated for these kinds of applications.
Core-shell colloidal materials with tailored structural, optical, and surface properties have been intensely investigated over the last decade. The research in this area was driven by the potential applications of such colloids in a wide range of fields. Most of the research effort has concentrated on changing the surface properties of a given particle by coating or encapsulating it within a shell of a different material. The core may be a metal oxide, a semiconductor, a quantum dot, a magnetic particle, a crystalline particles etc., while the shell usually changes the charge, the functionality, and the reactivity of the particle surface, and may also enhance the stability and dispersibility of the colloidal core. In other words, the material of core is different from shell materials, and the most commonly reported core-shell structures are ceramic core with polymer shell, or vice versa. Ceramic cores containing encapsulated actives and coated with a different kind of ceramic materials have also been reported in the literature.
Several methods have been reported in the literature to grow ceramic particles using sol-gel synthesis via W/O microemulsion. One such method depends on obtaining a larger particle size by adjusting the synthesis parameters. Although the particle size can be adjusted by controlling parameters such as the precursor concentration, water concentration, pH, temperature, ion strength, reaction time, there is a limitation on the particle growth. It is difficult using this method to produce monodisperse particles larger than 100 nm due to the intrinsic characteristics of the reverse micelles. Another method reported in the literature consist in extracting the particle seeds, drying them and then redispersing these seeds in a fresh W/O microemulsion, followed by the addition of more alkoxide precursors to grow the particles. There are two shortcomings regarding this method. First, during the extraction and drying steps the particles can aggregate irreversibly into micron size agglomerates, and second, the procedure introduces an additional separation step to recover the solid particles from liquid, which can significantly decrease the overall yield. Yet another process that can be used to increase particle size is described in FIG. 2. However, in this case the active molecules can only be encapsulated in the core. In addition the particles growth is limited by the fact that the alkoxide precursor needs to consume water for reaction. Since the amount of water is dictated by the formation of W/O microemulsion, only a limited supply of water is available. In fact, not all of the water introduced in the system is available for sol-gel reaction, as some water is bonded to the surfactant. As more alkoxide is being added more water is being consumed and less is available for further hydrolysis and growth.
There is therefore a need for a layered nanoparticle in which a dopant is located in, and restricted to, the core of the nanoparticle and/or one or more of the layers surrounding the core, and for a process for making such a nanoparticle. There is also a need for a process capable of making core-shell ceramic nanoparticles with more than one encapsulated molecular species (dopant) or with the active (dopant) encapsulated in different discrete locations or layers (i.e. shells). Such a process may open up a wide range of novel potential applications such as optical storage, data encryption or security ink in addition to the controlled release of drugs described above.